Metabolic and molecular consequences of reduced GLUT4 expression in the mouse

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To test the hypothesis that GLUT4 plays an important role in glucose homeostasis, the murine GLUT4 locus was disrupted using homologous recombination in embryonic stem cells. Both homozygote and heterozygote GLUT4 mutant mice are viable and display significant phenotypic changes. Surprisingly, GLUT4 null mice maintain near normal blood glucose levels. Hyperinsulinemia is seen in both sexes in the fed state. After an initial bolus of glucose, GLUT4 null mice eventually clear glucose as efficiently as controls. These mice also exhibit a decreased response to insulin during an insulin tolerance test. Based on serum metabolite and hormone levels GLUT4 null mice have altered glucose and fat metabolism. Homozygote mice display a significantly reduced lifespan, most failing to reach 6 months of age. Physically, GLUT4 null mice exhibit significant growth retardation from the second week of life onward. The growth retardation is more significant in the male GLUT4 null mice. Both sexes upon necropsy have severely enlarged hearts and significantly reduced adipose stores.;In contrast to GLUT4 null mice, male heterozygous mice display diabetic characteristics. In the fed state, the GLUT4 +/{dollar}-{dollar} mice possess significantly elevated blood glucose and insulin levels. However, female heterozygote mice do not exhibit hyperglycemia in the fed state. Both male and female heterozygote mice have normal glucose and insulin levels after a 16 hour fast.;The hearts of both heterozygote and homozygote GLUT4 mutant mice exhibit significant pathologies. physiologically, male heterozygote mice have borderline hypertension, whereas female heterozygote mice have only a moderate increase in blood pressure. Homozygote mice of both sexes do not have hypertension. The pathologic consequences of having a reduced amount of GLUT4 or no GLUT4 are quite significant. Histologically, both genotypes lead to fibrosis and calcification of the heart. Cardiomyocytes from heterozygole and homozygote are hypertrophied. Additionally, homozygote hearts display significant hypercellularity, interstitial hyperplasia, thickening of the vascular walls, and infiltration of inflammatory cells. These pathologic changes explain in part why the homozygote hearts weigh 2-3 times more than controls.;Both heterozygous male and homozygous animals show severe insulin resistance when in vitro glucose uptake is measured using maximal amounts of insulin in both soleus and extensor digitorum longus (EDL) muscles. These muscles contain the different muscle fiber types in the body and were used as an indication of total skeletal muscle insulin resistance. In GLUT4 null mice, in vitro glucose uptake is completely inhibited by cytochalasin B. Unlike insulin which stimulates GLUT4 null female soleus muscles to take up (2-{dollar}\sp3{dollar}H) deoxyglucose (2DOG), hypoxia fails to stimulate 2DOG uptake in all GLUT4 null muscles studied. Surprisingly, the GLUT4 null soleus and EDL muscles had an increase in oleate oxidation. (Abstract shortened by UMI.).